ABSTRACT Humans with sepsis often develop evidence of progressive brain dysfunction with intensity that leads to poor prognosis. There are few data that define molecular events causing brain dysfunction in sepsis. We have recently shown that complement activation products (C5a) and their receptors (C5aRs) are linked to the adverse effects of sepsis that cause significant organ damage. This complication is also linked to extracellular histones released from neutrophils, which cause organ failure and mortality during sepsis. The pathological substrate for sepsis-associated brain injury includes excessive activation of microglia, blood-brain barrier (BBB) dysfunction, impaired cerebral perfusion and alerted neurotransmission with additive factors like prolonged inflammation, severe hypoxemia, persistent hypoglycemia and aging, having an aggravating role in sepsis-related brain damage. BBB breakdown is considered a focal point in the development and progression of sepsis-associated brain damage. Although significant effort has been made to define the mechanism and risk factors involved in sepsis-related brain injury, the intra- and intercellular pathogenic mechanisms responsible for vascular injury are still largely unknown. The proposed study is designed to elucidate critical molecular mechanisms associated with BBB dysfunction in sepsis in aged mice. It will highlight the critical role of axis complement activation product C5a / C5aR1 and extracellular histones in BBB disruption and brain injury progression during sepsis in aged mice. Specifically, the following objectives will be evaluated: a) the effect of aging on innate immune responses and extracellular histone production in sepsis, b) the role histones in BBB and brain dysfunction in sepsis in aged mice, c) the mechanism underlying the BBB dysfunction in sepsis in aged mice; and d) how the histone inhibition affects the BBB and brain dysfunction in the post-septic condition. Collectively, the proposed studies may suggest therapeutic interventions to curtail harmful effects of sepsis in aging in the human brain.